Functional pH-Responsive Nanoparticles for Immune Reprogramming in MSS Colorectal Cancer via ER Stress-Induced Proteostasis Disruption, PD-L1-Targeting miRNA, and TLR7 Activation

  • Pharmaceutics. 2025 Nov 20;17(11):1503. doi: 10.3390/pharmaceutics17111503.
Yu-Li Lo  1  2  3 ,  Hua-Ching Lin  4  5 ,  Ching-Yao Li  1 ,  Bryant Huang  1 ,  Ching-Ping Yang  1  6 ,  Hui-Yen Chuang  7 ,  Tsui-Fen Chou  8  9
Affiliations
  • 1. Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 2. Faculty of Pharmacy, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 3. Research Fellow, Taipei Veterans General Hospital, Taipei 112, Taiwan.
  • 4. Division of Colorectal Surgery, Cheng-Hsin General Hospital, Taipei 112, Taiwan.
  • 5. Department of Healthcare Information and Management, Ming Chuan University, Taoyuan 320, Taiwan.
  • 6. Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 412, Taiwan.
  • 7. Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 8. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • 9. Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, USA.
PMID: 41304839 DOI: 10.3390/pharmaceutics17111503
Abstract

Background: Colorectal Cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 Inhibitor), miR-142 (a PD-L1-targeting MicroRNA), and imiquimod (R, a TLR7 Agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG-PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG-PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving Apoptosis and Autophagy, while miR-142 suppressed PD-L1 expression and epithelial-mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4+ and CD8+ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors.

Keywords
colorectal cancer; endoplasmic reticulum stress; immune checkpoint modulation; solid lipid nanoparticles; tumor microenvironment.
Products